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After reading the paper presented by Costa et al (Gut 2005;54:364–8) and the additional commentary by Pardi and Sandborn (Gut 2005;54:321–2), we would like to underscore the potential importance of biomarkers to assess intestinal inflammation and we would like to add a clarification on the faecal calprotectin assay.
We agree with Pardi and Sandborn that other serological markers have not demonstrated clinical utility as predictors or monitoring tools of inflammatory bowel disease (IBD) activity.1 Studies are emerging to support the sensitivity and clinical utility of more selective and specific non-invasive markers of intestinal inflammation, such as faecal calprotectin.2,3 As we deepen our understanding of the molecular basis of IBD, we may find that the degree of inflammation and its role in recurrence differs between Crohn’s disease and ulcerative colitis. This is an important question raised in both articles.
When comparing the Costa study with the earlier paper by Tibble and colleagues,4 one must ensure that the patient populations for each of the two disease states are equivalent. Disease activity was assessed by the Crohn’s disease activity index (CDAI), a test that is highly subjective and correlates poorly with inflammatory activity assessed by In111 labelled white cells and endoscopic indices, both objective markers of disease activity. It is also clear from a recent analysis by Sands and colleagues5 that there is wide variation in how researchers apply the parameters of the CDAI. Saverymuttu6 compared the excretion of In111 labelled leucocytes and found that the CDAI underestimated the degree of inflammation in 89% of patients with a CDAI <150 (that is, in clinical remission). This suggests that the CDAI does not necessarily reflect the inflammatory component of IBD.
In the Costa study (an unusually high) 71% of Crohn’s patients had small intestinal disease alone, with only 31% having ileocolitis or colitis. These values are compared with 47% and 53%, respectively, in the Tibble study. Thus we see different cohorts of Crohn’s patients being evaluated in the two, apparently similar, studies. Given the significant variability in CDAI, lack of correlation of CDAI with inflammation, and unmatched patient cohorts, it is not surprising that there is a difference in the results of the Costa study in comparison with Tibble’s previous trial.
Both studies (Tibble and Costa) demonstrate the clinical utility of faecal calprotectin in predicting remission in ulcerative colitis. Neither study makes clear the ability of biomarkers to predict remission in small bowel Crohn’s. CDAI as a marker of remission adds further confusion. The level of inflammatory biomarkers may vary anatomically, based on neutrophilic flux, chemotaxis, surface area, and disease process. Saverymuttu6 found higher levels of In111 labelled leucocytes among large bowel Crohn’s compared with Crohn’s in the small bowel. Assessment of calprotectin as a predictor of relapse in small intestinal Crohn’s is an issue for future investigation, utilising objective evaluation of intestinal inflammation.
Finally, in addition to potential selection bias in the specificity and predictive value of calprotectin in small bowel Crohn’s disease, there is also an important misunderstanding regarding assay performance that should be clarified. The studies published by Tibble and colleagues2,4 and most studies reported before 2003, evaluated faecal calprotectin using an earlier stool extraction process.7 The anti-calprotectin antibodies used in the earlier assay come from the same source. Eurospital has since developed an ELISA kit using the new extraction procedure and known calprotectin standards. The updated extraction process gives a five times higher yield during extraction of faecal calprotectin8 but does not change the performance of the kit in any other way. Thus the results in the Costa study should be effectively compared with a calprotectin cut off point of 250 mg/l, correcting Pardi and Sandborn’s puzzlement regarding the decline in NPV differences as the calprotectin cut off point “appeared” to decrease. Effective translation of values from the older calprotectin literature will help to clarify any confusion about the meaning of a given value. The new extraction process effectively removes nearly 100% of the calprotectin protein from the cytosol of neutrophils, thus maximising its sensitivity and reproducibility as a marker of intestinal inflammation.9
We encourage a broader use of these biomarkers as a clinical end point in future studies of the natural history and treatment of IBD.10 The role of inflammatory biomarkers in mucosal healing will be an important parameter to evaluate effective treatment for IBD.11 We thank the authors for their commitment to, and input in, this important effort.
Conflict of Interest: Dr. Hanaway works for Genova Diagnostics, who perform the calprotectin assay. Dr. Roseth is on the Board of CalproAS, who produce the PhiCal? kit.
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